# Neurophysiology of Orofacial Pain - Neurophysiology of Orofacial Pain Koichi Iwata, Mamoru Takeda, Seog

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• Neurophysiology of Orofacial Pain

Koichi Iwata, Mamoru Takeda, Seog Bae Oh, and Masamichi Shinoda

Abstract It is well known that unmyelinated C-fibers and small-diameter Aδ-fibers innervate the orofacial skin, mucous membrane, orofacial muscles, teeth, tongue, and temporomandibu- lar joint. Peripheral terminals consist of free nerve endings, and thermal and mechanical receptors such as transient receptor potential (TRP) channels and purinergic receptors exist in nerve endings. Ligands for each receptor are released from peripheral tissues following a variety of noxious stimuli applied to the orofacial region and bind to these receptors, following which action potentials are gener- ated in these fibers and conveyed mainly to the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2).

Neurons receiving noxious inputs from the orofacial regions are somatotopically orga- nized in the Vc and C1-C2. The third branch (mandibular nerve) of the trigeminal nerve innervates the dorsal portion of the Vc, and the first branch (ophthalmic nerve) of the tri- geminal nerve innervates the ventral part of the Vc; the middle portion of them receives the second branch (maxillary nerve) of the trigem- inal nerve. Various neurotransmitters such as glutamate and substance P (SP) are released from primary afferent terminals and bind to receptors such as AMPA and NMDA gluta- mate receptors and neurokinin 1 receptors in Vc and C1-C2 nociceptive neurons. Further, noxious information from the orofacial region reaching Vc and C1-C2 is sent to the somato- sensory and limbic cortices via the ventral pos- terior medial thalamic nucleus (VPM) and medial thalamic nuclei (parafascicular nucleus, centromedial nucleus, and medial dorsal nucleus), respectively, and finally, orofacial pain sensation is perceived. It is also known that descending pathways in the brain act on Vc and C1-C2 nociceptive neurons to modu- late pain signals. Under pathological condi- tions such as trigeminal nerve injury or orofacial inflammation, trigeminal ganglion (TG) neurons become hyperactive, and a bar- rage of action potentials is generated in TG neurons, and these are sensitized a long time

K. Iwata (*) • M. Shinoda Department of Physiology, School of Dentistry, Nihon University, Tokyo, Japan e-mail: iwata.kouichi@nihon-u.ac.jp; shinoda.masamichi@nihon-u.ac.jp

M. Takeda Laboratory of Food and Physiological Sciences, Department of Food and Life Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Kanagawa, Japan e-mail: m-takeda@azabu-u.ac.jp

S.B. Oh Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, Republic of Korea e-mail: odolbae@snu.ac.kr

# Springer International Publishing AG 2017 C.S. Farah et al. (eds.), Contemporary Oral Medicine, DOI 10.1007/978-3-319-28100-1_8-3

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mailto:iwata.kouichi@nihon-u.ac.jp mailto:shinoda.masamichi@nihon-u.ac.jp mailto:m-takeda@azabu-u.ac.jp mailto:odolbae@snu.ac.kr

• after the hyperactivation of TG neurons. Fur- thermore, there is an increase in Vc and C1-C2 neuronal activities, and these neurons can be sensitized in association with TG-neuron sen- sitization, and then orofacial pain hypersensi- tivity can occur. Recent studies have also reported that glial cells are involved in patho- logical orofacial pain states related to trigemi- nal nerve injury and orofacial inflammation. Peripheral and central mechanisms of orofacial pain under physiologic and pathologic condi- tions are overviewed in this chapter, and future insights regarding the pathogenesis of persis- tent orofacial pain are discussed.

Keywords Trigeminal nerve •Orofacial pain •Brainstem • Medial system • Lateral system • Descending modulation • Persistent pain

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Primary Afferent Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Physiology of Orofacial Nociceptors . . . . . . . . . . . . . . . . . 3 Receptor Mechanisms of Trigeminal Primary

Afferent Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Trigeminal Ganglion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Pathological Changes in Trigeminal Ganglion . . . . . . . 6

Brainstem Nociceptive Neurons . . . . . . . . . . . . . . . . . . . . 7 Trigeminal Spinal Nucleus and Upper Cervical

Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Physiology of Trigeminal Nociceptive Neurons . . . . . 10 Neurotransmitters in Brainstem Nociceptive

Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Pathological Changes in Brainstem Nociceptive

Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Higher Brain Function Regulating Orofacial Nociception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Ascending Orofacial Pain Pathways . . . . . . . . . . . . . . . . . . 14 Sensory-Discriminative and Motivational and

Affective Aspects of Pain . . . . . . . . . . . . . . . . . . . . . . . . . 14 Human Brain Function for Orofacial Pain

Sensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Descending Modulation of Orofacial Pain . . . . . . . . . 16 Descending Pathways Influencing Orofacial Pain . . . . 16 Modulation of Trigeminal Nociceptive Neurons . . . . . 17 Pathological Changes in the Descending System . . . . 17

Conclusion and Future Directions . . . . . . . . . . . . . . . . . . 18

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Introduction

The trigeminal nervous system is known to have unique structures and functions for processing orofacial nociception as well as non-noxious sen- sations in comparison to the spinal nervous sys- tem. Oral mucous membrane, tongue, tooth pulp, gingiva, and temporomandibular joints are inner- vated by small-diameter Aδ-fibers and unmyelin- ated C-fibers that process orofacial nociception. Peripheral terminals of these fibers are composed of free nerve endings, and various receptors are expressed on the membrane surface of nerve end- ings, and these receptors act as sensors responding to various noxious stimuli such as heat, cold, or chemical stimulus (Iwata et al. 2011a). For exam- ple, it has been well documented in recent decades that transient receptor potential vanilloid 1 (TRPV1) channel is cloned, and functions of this channel have been evaluated (Mickle et al. 2015). TRPV1 and TRPV2 channels are known to be involved in heat sensation and TRPV3 and TRPV4 in a warm sensation, whereas transient receptor potential ankyrin 1 (TRPA1) and M8 are known to participate in cool and cold sensa- tions (Tominaga 2007). ATP and glutamate recep- tors have also been reported to be expressed in free nerve endings of C-fibers and are known to contribute to orofacial nociception (Sessle 2011). Though piezo receptors have been reported to take part in mechanical sensations, detailed mecha- nisms for mechanical sensation are still unknown (Woo et al. 2014).

Neuronal activity is conveyed along the affer- ents to the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2), and nociceptive neurons in these areas are activated following various noxious stimuli applied to the orofacial regions (Sessle 2000). Vc and C1-C2 nociceptive neurons are classified as wide dynamic range (WDR) and nociceptive-specific (NS) neurons according to their response proper- ties to mechanical stimulation of the receptive fields (Iwata et al. 1999, 2001). The nociceptive information is then conveyed to the somatosen- sory and limbic cortices via the ventral post- eromedial thalamic nucleus (VPM) and medial

2 K. Iwata et al.

• thalamic nuclei, respectively. The VPM-somato- sensory pathway is known to be involved in the sensory-discriminative aspect of pain, whereas medial thalamic nuclei-limbic cortices pathways are involved in the motivational and affective aspect of pain, and some noxious information is also conveyed to the limbic cortices via the para- brachial nucleus (Treede et al. 1999; Benarroch 2001). At each level of ascending pathways, var- ious excitatory and inhibitory neurotransmitters are involved in synaptic transmission and modu- latory processes of orofacial nociceptive informa- tion. Projection neurons are known to express excitatory transmitters, whereas most of the local circuit neurons are inhibitory interneurons expressing inhibitory transmitters. Both excit- atory and inhibitory neurons are involved in the modulation of the neuronal excitability regarding orofacial nociception in higher central nervous system (CNS) regions. It is also well known that the descending system acts on nociceptive neu- rons at each level of the ascending pain pathways, and neuronal activity is modulated (Mason 2012). These ascending and descending pathways are thought to play a pivotal role involved in orofacial nociception.

Under pathological conditions, functional and morphological changes are known to occur in the peripheral and central nervous system. Notice- able shifts in the peripheral nervous system are the enhancement of neuronal activity and up- or downregulation of various molecules within the trigeminal ganglion (TG) associated with trigem- inal nerve injury or orofacial inflammation. It is well known that neuropeptides and potassium channels are downregulated in TG neurons fol- lowing nerve transection, whereas sodium chan- nels are upregulated and accumulated at the

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